Method and apparatus for manufacturing, filling and packaging medical devices and medical containers

ABSTRACT

Clean syringe barrels from forming device immediately transferred to a controlled environment to maintain a clean work area. The work area can be a clean room or localized area to avoid the need to maintain cleanliness levels in an entire room. A localized area uses a housing assembly having a HEPA filter coupled to an air inlet to filter the air entering the housing. An air blower is coupled to the air inlet to feed filtered air into the housing assembly and to maintain a positive air pressure in the housing assembly to prevent unfiltered outside air from entering. Syringe tip closures can be introduced into the housing assembly, where syringe barrels and tip closures are cleaned with filtered ionized air and the tip closures are coupled to the barrels. A thin coating of lubricant is applied to the inner surfaces of the syringe barrels. The syringe barrels or medical container can be filled with a substance and a closure member is attached. While still in the housing assembly the syringe barrels can be formed into an array and placed in a clean outer container. The outer container is then closed and sealed. The outer container and syringe barrels can be sterilized with heat, radiation or by exposure to a sterilizing gas.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of application Ser. No. 09/267,107filed Mar. 12, 1999 now U.S. Pat. No. 6,189,292, which claims thebenefit under 35 U.S.C. § 119(e) of U.S. provisional application SerialNo. 60/077,897 filed Mar. 13, 1998 and U.S. provisional applicationSerial No. 60/102,338 filed Sep. 29, 1998, which are hereby incorporatedby reference in their entirety.

FIELD OF THE INVENTION

The present invention relates generally to a method of manufacturingdrug delivery and drug container devices, such as syringe components,and packaging the components in a clean, substantially particulate-freearea. More particularly, the invention is directed to a method formanufacturing glass or plastic syringe barrels and assembling andpackaging the syringe barrels in a clean room or locally controlledenvironment which is clean and substantially free of airborneparticulates.

BACKGROUND OF THE INVENTION

Drug delivery devices are generally prepared by molding or shaping thevarious components and then assembling the components. The assemblingsteps and other processing operations typically produce a device thatsubsequently must be cleaned to remove particulates adhering to thesurfaces to satisfy cleanliness standards for drug delivery devices.After cleaning, the drug delivery devices are packaged and sterilized.

Syringes have been classified into several general types. The first typeis assembled and placed in sterile packaging which can be shipped with avial or ampoule of a drug or other injectable solution. The vial orampoule is generally made of glass or other clear material that does notinterfere with the stability of the drug during prolonged storage. Thesyringe is filled with the drug or other solution at the point of useand injected into the patient. Another type of syringe is packaged witha vial filled with a powdered or lyophilized drug which is dissolved inwater or other suitable solvent prior to charging into the syringe.

These syringes have the disadvantage of increasing the time anddifficulty of filling the syringe at the point of use with increasedpossibility of contamination of the syringe and/or drug solution. Thereis a further risk of glass particles from the ampoules contaminating thedrug solution when the ampoules are opened.

Several of these disadvantages are overcome by providing prefilledsyringes which can be filled with a suitable drug solution prior to use.Prefilled syringes, as the term is known in the art, are syringes thatare filled by the drug manufacturer and shipped to the health careprovider ready for use. Prefilled syringes have the advantage ofconvenience and ease of application with reduced risk of contaminationof the drug solution. A difficulty in producing prefilled syringes, ifthey are made of plastic rather than glass, is selecting suitablematerials that maintain their clarity for extended periods of time anddo not contaminate or react with the drug solution.

Syringes and other drug delivery devices are generally assembled andpackaged in clean rooms to maintain proper cleanliness levels. The cleanrooms are equipped with extensive filter assemblies and air controlsystems to remove particulates and pyrogens from the air in the room andto prevent particulates and pyrogens from entering the room. Theoperators and other personnel in the clean room are required to wearappropriate protective garments to reduce contamination of the air andthe drug delivery devices being manufactured or assembled. As people andequipment enter and leave the clean room, the risk of contamination andintroduction of foreign particulates and pyrogens increases.

Various operations are able to form clean and sterile drug deliverydevices. However, subsequent handling, filling and printing of the drugdelivery device can contaminate the device. It is then necessary toclean and sterilize the drug delivery device before use.

Accordingly, there is a continuing need in the industry for an improvedsystem for manufacturing and assembling clean and sterile medicaldevices and filling such devices.

SUMMARY OF THE INVENTION

The present invention is directed to a method and apparatus formaintaining a clean environment during the manufacture and assembly ofmedical devices such as drug delivery devices and medical containerdevices. More specifically, the invention is directed to the manufactureof various medical containers, drug delivery and drug container deviceswhich are clean and have a low bio-burden or are sterile at thecompletion of the manufacturing step and immediately transferring thedevices to a clean room or to a locally controlled environment tomaintain cleanliness levels while assembling and packaging the devices.The medical devices can be filled with a suitable substance such as,saline solutions, flush solutions or contrast agents, pharmaceuticalagents and vaccines, in either a dry or liquid state.

Accordingly, a primary object of the invention is to manufacture medicalcontainer devices immediately upstream of at least one housing assemblywhich defines a locally controlled environment. The medical containersare manufactured from glass or plastic under conditions which produce asubstantially clean and sterile part. The housing assembly receives themedical containers directly from the manufacturing apparatus without aprior cleaning step so that the containers can be assembled within thehousing assembly under controlled conditions to maintain predeterminedcleanliness standards for medical containers and devices.

Another object of the invention is to provide a method for manufacturinga substantially clean and low bio-burden medical containers, such as asyringe barrel and assembling the syringe barrel with variouscomponents, such as a tip closure or Luer lock, in a locally controlledenvironment without the need for a water washing step.

A further object of the invention is to provide a method and apparatusfor forming glass medical containers, such as drug delivery devices orcomponents, annealing the glass medical containers, and then immediatelycapturing the annealed container in an environmentally controlled areato maintain a predetermined cleanliness and low bio-burden. The annealedglass medical containers are captured from the annealing oven in amanner to maintain the cleanliness and low bio-burden to avoid amandatory cleaning step. The environmentally controlled area can be aclean room or a locally controlled environment.

Another object of the invention is to provide a method and apparatus forproducing clean medical containers and delivering the devices to ahousing assembly which defines a locally controlled environment, wherethe housing assembly includes a HEPA filter and a fan or blower to feedfiltered air into the housing and maintain the housing assembly atpredetermined cleanliness levels.

In embodiments of the invention, the medical containers are glasssyringe barrels, and particularly prefillable glass syringe barrels,manufactured by processes which produce substantially clean and lowbio-burden or sterile syringe barrels. The glass syringe barrels aremade from cylindrical glass tubes that are cut to a desired length. Thetubes are then fed to a forming machine which in one embodiment heatsthe ends of the tubes and forms a flange at one end and a tip at theopposite end. The glass syringe barrels are annealed by heating in aLehr or annealing oven to at least about 560° C. for an appropriate timeto relieve stresses in the glass. The annealing produces a clean and lowbio-burden syringe barrel which is then immediately transferred to anenvironmentally controlled area substantially without contamination.

A further object of the invention is to provide a housing assembly whichmaintains a locally controlled environment for assembling medicalcontainers and packaging an array of medical containers in closed secondcontainers. The medical containers can be sterilized in a subsequentstep.

The housing assembly defining the locally controlled environment can bea portable unit having a work surface for performing the desiredoperations manually or automatically. The work surface is enclosed byside panels, at least some of which are preferably transparent to allowviewing and inspection by an operator located outside the housing. Theassembly includes a top wall coupled to the side panels to define anenclosure. The assembly includes a fan or blower assembly and a filterassembly to direct filtered air into the housing and maintain a cleanenvironment and can be operated to maintain a positive pressure in thehousing assembly to prevent the infiltration of unfiltered air. Anoptional exhaust fan can also be provided to draw air downwardly throughthe housing assembly and exhaust the air without causing a negativepressure in the housing assembly.

In one embodiment of the invention, the medical containers exit theforming device and are immediately captured in an environmentallycontrolled area to maintain cleanliness. The medical devices, such assyringe barrels, in the housing assembly optionally can be cleaned bystreams of clean filtered air or ionized air when necessary. Thecleaning air removes substantially all particulates that may be adheredto the inner and outer surfaces of the barrel to attain the desiredcleanliness level. A vacuum exhaust can be provided in the area of thebarrel to carry the particulates away from the barrel and out of thehousing assembly. Tip closures, Luer locks or syringe needles with theirassociated needle sheaths are also supplied to the housing assemblywhere they can be cleaned with filtered air or ionized air. The tipclosures, Luer locks and needles are coupled to the syringe barrels. Alubricant is preferably applied to the inner surface of the syringebarrel, and the syringe barrels are placed in a grid or tray which is inturn placed in a container such as a tub. A plastic sheet is placed overthe tray and the tub is closed with a sheet of flexible material whichgenerally is heat-sealed to the tub. The tub is then enclosed in anouter wrap such as a plastic bag which is heat sealed. The tub, outerwrap and contents are sterilized by a sterilizing gas or radiation. Someor all of these operations can be conducted in a single housing assemblyor in a plurality of housing assemblies coupled together.

A method of producing prefillable, glass syringe barrels in accordancewith the present invention comprises the steps of supplying a glass tubeto a forming device and forming a hollow syringe barrel having a flangeat one end and a tip at the other end. The syringe barrels are annealedin a Lehr oven, cooled, and received in a first housing assembly havingan air filtering device to maintain a predetermined cleanliness leveltherein, and a plurality of tip closures are supplied to the firsthousing assembly and are assembled with the syringe barrels. A stream offiltered air is directed to the syringe barrels and syringe componentsto remove particulates therefrom and clean the outer surfaces thereof.The assembled syringe barrels and syringe components are conveyed to asecond housing assembly having a filtering device for maintaining apredetermined cleanliness level, and a lubricant is preferably appliedto the inner surfaces of the syringe barrels. In a third housingassembly, the syringe barrels are formed into an array and placed into acontainer having a closed bottom, side walls and an open top.Thereafter, the container is conveyed to a fourth housing assemblyhaving an air filtering device to maintain a predetermined cleanlinesslevel, and a closure is applied to the container to seal the container.

The aspects of the invention are further attained by providing a methodof producing a filled syringe comprising the steps of forming a plasticsyringe barrel in an injection molding machine where the syringe barrelhas a cylindrical side wall, an open proximal receiving end and afrustoconically shaped outlet nozzle at its distal end and transferringthe syringe barrel, without any additional cleaning or sterilization,into an environmentally controlled area to maintain a predeterminedcleanliness level. A stream of filtered air is directed toward thesyringe barrel in the environmentally controlled area to removeparticles from surfaces thereof to clean the syringe barrel. A tip capis delivered to the environmentally controlled area and the tip cap isassembled onto the outlet nozzle of the syringe barrel to close theoutlet nozzle and the syringe barrel is filled with a substance throughits open proximal end. A stopper is delivered to the environmentallycontrolled area and is inserted into the open proximal end of the barrelto form a prefilled syringe. The prefilled syringe is then removed fromthe environmentally controlled area. In further embodiments, a stopperis applied to the syringe followed by filling the syringe through thetip or nozzle and then closing with a tip cap.

These and other aspects, advantages and salient features of theinvention will become apparent to one skilled in the art from theannexed drawings and the following detailed description which disclosespreferred embodiments of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

Referring to the drawings which form a part of this original disclosure:

FIG. 1 is an exploded side elevational view of a glass syringe showingthe Luer locking collar;

FIG. 2 is an end view of the Luer locking collar of FIG. 1;

FIG. 3 is a side elevational view of an assembled syringe barrel in anembodiment of the invention;

FIG. 4 is a side elevational view of a plastic syringe in a furtherembodiment;

FIG. 5 is an exploded perspective view of a syringe barrel tub enclosurein an embodiment of the invention;

FIG. 6 is a flow chart of the manufacturing steps for forming glasssyringe barrels;

FIG. 7 is a top view of housing assemblies defining a locally controlledenvironment for cleaning, assembling and packaging syringe barrels inaccordance with one embodiment of the invention;

FIG. 8 is a perspective view of the locally controlled environment ofFIG. 7;

FIG. 9 is a flow chart of the assembly steps for packaging the syringebarrel assemblies;

FIG. 10 is a flow chart of the filling steps for filling syringe barrelsto produce prefilled syringes; and

FIG. 11 is a side elevational view of a glass forming and glassannealing apparatus coupled to a clean room for assembling and packagingthe syringe barrels in accordance with another embodiment of theinvention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention is directed to a method and apparatus formanufacturing and thereafter assembling and packaging medicalcontainers, drug delivery devices and drug containers, such as vials,syringe barrels and prefilled syringes, in a clean, environmentallycontrolled area. As used herein, medical containers for containingand/or dispensing substances include vials and injection devices such assyringes. In addition, as used herein, a substance includes, forexample, water, saline solutions, flush solutions and contrastingagents, pharmaceutical agents and vaccines in either a dry state orliquid state. The medical containers can be syringe barrels formed froma base material such as glass or plastic. The syringe barrels are usedto assemble a syringe 10 as shown in FIG. 1. Although embodiments of theinvention are disclosed as a hypodermic syringe assembly, it is withinthe purview of the present invention to include various other drugcontainers, such as plastic or glass cylindrical reservoirs havingresilient stoppers and/or closures at one or both ends, or other drugdelivery devices or appliances which require a clean environment duringmanufacture or assembly.

Referring to FIGS. 1 and 2, the medical container is a syringe 10including a glass syringe barrel 12, a plastic plunger rod and attachedrubber stopper or piston (not shown) and a tip closure 15 or needlesheath closure 16. In further embodiments, the syringe can be aneedleless syringe as known in the art. Syringe barrel 12 in theembodiment illustrated has a cylindrical side wall 18, a flange 20 at areceiving end 22, and a frustoconical outlet nozzle 24 at a dischargeend of a barrel tip 26. A Luer locking collar 28 encircles the outletnozzle 24 to define an annular space 30 surrounding the outlet nozzle24. Side wall 18 can include suitable printed indicia for indicating thevolume of the syringe, the name of the manufacturer and the like.

Luer locking collar 28 is generally a plastic collar that is able to besnapped onto the nozzle 24 of the syringe barrel tip 26. As shown inFIGS. 1 and 2, Luer locking collar 28 includes an annular sleeve 30having an inner wall 32 with internal threads 34. The annular sleeve 30has an open end 36 for coupling with an externally threaded member. Thesleeve 30 further has a base end 38 with a plurality of flexible tabs 40extending radially inwardly toward the center axis of the sleeve 30 todefine an opening 42. The tabs 40 are sufficiently flexible to deflectout of the plane of the tabs along an axial direction to snap into arecess 44 on the tip 26 of the syringe barrel 12. In the embodimentillustrated, four tabs 40 are included which are spaced apart around thesleeve 30 by radial gaps. The inner edges 46 of the tabs 40 have anarcuate shape complimenting the shape of the syringe barrel tip 26. Theouter surface of the sleeve 30 includes longitudinal ribs 48 forgripping and rotating the Luer locking collar 28 with respect to thesyringe barrel 12.

Although the syringe barrel illustrated in this embodiment includes alocking Luer-type collar 28, it is within the purview of the presentinvention to include syringe barrels without a collar, syringe barrelshaving an eccentrically positioned nozzle, and various other nozzle-likestructures adapted to accept, either permanently or removably, a needlecannula or needle cannula assembly. It is only required that there is anaperture on the distal end of the syringe barrel in fluid communicationwith the interior of the syringe barrel. In addition to the tip closureand needle closure illustrated in this embodiment, it is also within thepurview of the present invention to include a wide variety of closuresfor sealing a syringe barrel or drug container including, but notlimited to, cannula occluding plugs, removable seals attached byadhesive or heat sealing, threaded closures and the like. In furtherembodiments, the syringe barrel is a cylindrical tube having plasticcomponents attached to each end forming a thumb flange and a nozzle,respectively.

A plunger rod and a stopper or piston can be provided for assemblingwith the syringe barrel to manufacture prefilled syringe barrels. Thestopper is typically made of a molded flexible material, such as rubber,that is sufficiently pliable and flexible to readily conform to theinner surface of the syringe barrel and form a fluid tight seal. Theplunger rod is typically made of plastic.

Tip closure 15 is dimensioned to close the frustoconical nozzle 24 ofsyringe barrel 12. Referring to FIG. 1, tip closure 15 has a slightfrustoconical sleeve 49 with a closed end 50 and an outer annular flange52. Sleeve 49 is dimensioned to fit securely over frustoconical nozzle24. Tip closure 15 is typically made from flexible rubber-likematerials, rigid materials or peelable strip materials as known in theart.

Referring to FIG. 3, a further embodiment includes a glass syringebarrel 13 having a tapered outlet nozzle tip 17 with an enlarged end 19,a side wall 21 and a flange 23. A protective plastic needle sheath 16has an open end 64 for coupling with syringe tip 17 and a closed end 66opposite open end 64. Protective sheath 16 has a hollow, substantiallycylindrical shape and can be dimensioned to receive a needle 60. In theembodiment illustrated, sheath 16 contacts and closes off the tip ofneedle 60 to prevent fluid leakage. In further embodiments, the sidewalls 68 are spaced from needle 60 so that sheath 62 does not contactneedle 60. The needle 60 can be a stainless steel needle secured in thetip 17 by a suitable adhesive as known in the art.

FIG. 4 illustrates an embodiment where the medical container is asyringe 10′ including a plastic syringe barrel 12′, a plastic plunger14′ and a plastic tip closure 15′ . In further embodiments, syringe 10′can be a needleless syringe or include a needle tip closure as known inthe art. Syringe barrel 12′ has a cylindrical sidewall 18′, a flange 20′at a receiving end 22′, and a frustoconical outlet nozzle 24′ at adischarge end 26′. Collar 28′ encircles the outlet nozzle 24′ to definean annular space 30′ surrounding the outlet nozzle 24′. An inner surfaceof collar 28′ includes a threaded portion 32′. Sidewall 18′ can includesuitable printed indicia for indicating the volume of the syringe, thename of the manufacturer and the like.

Plunger 14′ includes a molded flexible stopper 34′ having afrustoconical end face 35′, and a plurality of annular ridges 36′dimensioned to form fluid tight contact with the inner surface 19′ ofsidewall 18′ of syringe barrel 12′. A plunger rod 37′ includes inthreaded member 38′ which is coupled to an internally threaded recess40′ in stopper 34′. Plunger rod 36′ has four vanes 42′ extendingoutwardly from a center longitudinal axis and extending at substantiallyright angles to each other and at a flat plate 44′ for pushing theplunger rod 37′ through syringe barrel 12′.

Referring to FIG. 5, a plurality of syringe barrel assemblies 12 areplaced in a container or tub package 82. In the embodiment illustrated,the syringe assemblies include a syringe barrel 12, a Luer lockingcollar 28 and a tip cap 15. In further embodiments, the syringe barrelassemblies can include a needle cannula and sheath as shown in FIG. 3.The syringe barrel assemblies can be placed in any suitable package orcontainer depending on the particular syringe and its end use. A tray 84is provided having a plurality of spaced-apart openings 86 and collars88 extending upward for supporting the syringe barrels 12. In theembodiment illustrated, openings 86 and collars 88 are arranged in aseries of rows and columns and are uniformly spaced apart. Tray 84includes cut-out portions 90 for lifting and easily gripping the tray 84and to orient the tray during various processing and filling operations.Tray 84 is nested in a suitable container such as a tub 92. Tub 92includes side walls 94 and a bottom wall 96. A stepped portion 98 of tub92 is formed in side walls 96 to support tray 84 so that the ends ofsyringe barrels 12 can be spaced from bottom wall 96. In otherembodiments, the ends of syringe barrels can contact bottom wall 96. Aperipheral flange 100 extends outward from the open top end of sidewalls 94. Tub 92 is typically an integrally formed rigid plastic unitmade by a suitable molding process, such as injection molding, vacuumforming or blow molding.

Tray 84 supports an array of syringe barrels 12 and is positioned in tub92. A protective layer of sheet material 102, such as polyethylene, foamor other plastic, is positioned to cover tray 84 and the syringe barrels12. Preferably, sheet 102 is substantially the same size as tray 84. Aclosure or cover sheet 104 is then positioned on peripheral flange 100and is sealed on the flange to completely enclose the array of syringebarrels 12. The tub 92 is then enclosed in a sealed plastic bag orwrapper. Typically, the cover sheet 104 is a thermoplastic material thatis heat-sealed to flange 100 to form a complete seal. A suitable coversheet 104 is a gas-permeable material such as a spun bonded polyolefinsold under the trademark TYVEK by E.I. DuPont & Co. This allows thesyringe barrels 12 to be gas sterilized, if desired, while they are inthe sealed tub 92. In further embodiments, the syringe barrels can besterilized by radiation.

The syringe of FIGS. 1-4 can be assembled by the manufacturer andpackaged in suitable clean and sterile packaging. The syringes may bepackaged individually or in bulk. One example of bulk packaging places aplurality of the syringe barrels laying flat in a molded tray. Aplurality of the trays are stacked in a carton which is then closed andsterilized. In embodiments of the invention, the syringe components arepartially assembled so that prefilled syringes can be produced by thecustomer, such as a pharmaceutical manufacturer or contract filler. Anobject of the invention is to provide a method for manufacturingprefillable syringe components for filling with a substance and forassembling the barrels and tip closures of the syringes.

Syringe barrels 12 can be manufactured using various plastic or glassforming techniques as known in the art. Plastic medical containers canbe made by conventional injection molding devices from polyolefins suchas polypropylene. Although syringe barrels and other components can bemanufactured using molding or forming techniques that produce lowbio-burden or sterile components, subsequent handling of the componentsoften results in contamination that requires additional cleaning andsterilization. The present invention avoids this problem.

Syringe barrels 12 in embodiments of the invention are made of glass.The glass syringe barrels are formed and annealed and then captured in aclean, locally controlled environment or clean room immediately uponbeing ejected or discharged from the annealing oven to maintain thesyringe barrels in a substantially clean condition having lowbio-burden. Glass and molded plastic drug containers and syringe barrelsare typically molded at sufficient temperatures and conditions toproduce clean and low bio-burden devices. The clean and low bio-burdensyringe barrels are captured in an enclosed housing assembly to maintaincleanliness and low bio-burden without exposing to unfiltered air andcontaminants.

The glass syringe barrels are manufactured by the steps as shown in theflow chart of FIG. 6 using standard glass forming techniques andequipment. Referring to FIG. 6, a glass tube or “cane” having a workinglength and a diameter corresponding to the diameter of the finishedsyringe barrel is provided from a supply indicated in block 220. Theglass tubes can be heated in a Lehr oven of at least about 560° C. foran appropriate length of time to anneal the glass, although annealing isgenerally not necessary at this stage. The glass tubes are then cut to aworking length as indicated in block 222 and are fed to a syringe barrelforming device. The syringe barrel forming device heats the ends of theglass tube to a softening temperature and forms a thumb flange at theproximal end and an outlet nozzle tip at the distal end as indicated inblock 224. The temperature of the glass during the tip and flangeformation is generally about 760°-1100° C. The formed glass syringebarrels are then heated in a Lehr oven to at least about 560° C. for anappropriate length of time to anneal the glass and relieve stresses inthe syringe barrel as indicated in block 226. The length of time for theannealing is dependent on the particular glass being used and theannealing temperature as known by those skilled in the art. Thereafter,the syringe barrels are cooled and immediately transferred to a cleanenvironment for maintaining a clean and low bio-burden condition asindicated in block 228. Alternatively, the annealed syringe barrels canbe cooled in the clean environment. The syringe barrels can be thenformed into an array and packaged as indicated in block 230.

It has been found that glass syringe barrels exiting a Lehr oven atabout 590° C. have satisfactorily low particulate levels on theirsurfaces to meet drug delivery device cleanliness standards. Testresults have shown that barrels after heating at 590° C. for about 30minutes have an average of 8.55 particles per barrel with a particlesize of about 5-24 microns, with the barrels being substantially free ofparticles having a particle size of 25 microns or larger. Tests havealso demonstrated that the syringe barrels have satisfactory sterility,toxicity and pyrogenicity levels as determined by standard testingprocedures for drug delivery devices.

In embodiments of the invention, the syringes are preferably prefillablesyringes as known in the art having an internal volume of about 0.3-60ml. The syringe barrels 12 are made of glass suitable for long termstorage of a drug solution.

In an embodiment of the invention, the syringe barrels and the barrelassembly tub package 84 are produced using an apparatus 108 depicted inFIGS. 7 and 8 by the method outlined in the flow charts of FIGS. 6 and9. The apparatus 108 in the embodiment shown includes several modularhousing assemblies 112, 114, 116 and 118 which are coupled together.Preferably, the housing assemblies are modular and portable so that theycan be separated from one another for repair or replacement. Inaddition, modular assemblies permit expansion or reduction in overallsize, as well as reconfiguration, to accommodate the particular needs ofthe overall operation. The modular housing assemblies can be coupledtogether directly or by intermediate housings or tunnels to preventinfiltration of unfiltered air.

The housing assemblies are substantially alike, although they can differin size or shape to accommodate the specific assembly step beingperformed. For purposes of illustration, housing assembly 112 is shownwhich includes side walls 120, some or all of which may be made of glassor other transparent materials, completely surrounding a work space 122.It will be appreciated that housing assemblies 112, 114, 116 and 118 aresubstantially similar. A top member 124 is coupled to side walls 120 toenclose work space 122. Top member 124 has an air blower 126 and iscoupled to a high efficiency particulate air filter (HEPA) 128 to directfiltered air into the housing assembly. Preferably, air blower 126maintains a positive pressure in work space 122 to prevent infiltrationof contaminated air. The efficiency of the HEPA filter determines thelevel of particulates and viable and non-viable particulates andpyrogens in the air in the work space 122. In a preferred embodiment ofthe invention, filter 128 removes particles of 0.3 microns or larger. Inother embodiments, particles smaller than 0.3 microns can also beremoved.

In one embodiment of the invention, the HEPA filters are selected tomaintain the housing assemblies and the respective work spaces thereinat levels meeting or exceeding Class 100 conditions with respect toparticulates as defined by Federal Standard No. 209E, “AirborneParticulate Cleanliness Classes in Clean Rooms and Clean Zones”,approved by the General Services Administration (Sep. 11, 1992). Inother embodiments, the HEPA filters are selected to maintain cleanlinessstandards as needed which can be higher or lower than Class 100.

Air blower 126 directs clean filtered air downward through the housingassembly to an outlet (not shown) in the lower end of the housingassembly. An optional exhaust fan 127 can be included to draw air andany particulates or other contaminants out of the housing assembly. Oneor more of the side walls 120 can include an optional access opening 129as shown in enclosure 116 to enable an operator to reach into theworkspace and perform various operations. As shown in FIG. 7, a chair131 or stool is provided for the operator. A positive pressure ispreferably maintained in the workspace 122 to prevent air from enteringthrough the access opening 129.

In the embodiment illustrated, the glass syringe barrels are formed inthe glass forming apparatus 161 from glass cylinders. The formed glasssyringe barrels are transferred to a Lehr oven 162 where the barrels areheated to at least 560° C. to anneal the glass and to relieve thestresses in the glass produced as a result of the barrel forming steps.The syringe barrel forming apparatus 160 is generally not enclosed in aclean area. The syringe barrels can be transferred directly to the Lehroven 162 by a conveyor 164 passing through an opening 166 or the barrelscan be transferred manually. In still further embodiments, the syringebarrels are transferred to a storage bin for a subsequent heating stepin a Lehr oven.

After the glass syringe barrels are annealed in the Lehr oven 162, thesyringe barrels exit through a tunnel 168 or other enclosure to maintaincleanliness and low bio-burden levels. In preferred embodiments, aconveyor 170 carries the finished glass barrels from the Lehr oven 162through the tunnel 168 to the packaging and assembling apparatus 108.Alternatively, a robotic mechanism can be used to transfer the syringebarrels from a molding or annealing apparatus to a housing assembly. Anoptional printing apparatus 172 is provided downstream of the Lehr oven162 to print indicia on the syringe barrel before assembling andpackaging.

The housing assemblies shown in FIGS. 7 and 8 are coupled to an adjacenthousing assembly in a manner to maintain a clean locally controlledenvironment. As shown, tunnel-like enclosures 141 are attached to theside walls 120 to carry the syringe barrels or other drug deliverydevices from one housing assembly to another without exposure to outsideair. An air blower and appropriate HEPA filter (not shown) can beprovided in enclosure 141 as needed to maintain desired cleanlinesslevels.

Referring to FIG. 7, housing assembly 112 encloses an apparatus 133 forassembling the syringe barrels 12 with the selected component, such as atip closure, needle cannula, Luer lock collar and needle sheath. Thesyringe barrels 12, which can be printed or unprinted, are essentiallyclean when fed directly from the Lehr oven 162. The syringe barrels arefed from the Lehr oven 162 or other supply to a recess 132 in a rotatingtable 134. Table 134 rotates to station 135 where clean components arefed from a supply entrance 136 and coupled to the ends of the syringebarrels 12 to produce a syringe barrel assembly 137 as shown in FIG. 1.The table 134 continues to rotate to station 138 where the syringebarrel assembly 137 is ejected onto a conveyor rail 140. Conveyor rail140 is enclosed in a tunnel 141 to maintain the same cleanliness levelsas in housing assembly 112. Preferably, the syringe barrel assemblies137 are substantially clean and have a sufficiently low bio-burden sothat further washing or cleaning steps can be eliminated. In embodimentswhere further cleaning is necessary, however, syringe barrel assemblies137 are conveyed past nozzles 142 which direct streams of filtered,ionized air across the conveyor rail 140 to remove any particulates fromthe outer surfaces of syringe barrel assemblies 137 and to reduce staticcharge. Conveyor rail 140 has a discharge end 144 in housing assembly114.

Housing assembly 114 contains a rotating table 146 having recesses 148for receiving syringe barrel assemblies 137 from the conveyor rail 140.Table 146 rotates to carry the syringe barrel assemblies 137 to acleaning station 150 where streams of filtered, ionized air are directedinto the syringe barrel assemblies 137 to loosen and remove anyparticulates from their inner surfaces while a vacuum is applied to theinner surface to carry the particulates away. In preferred embodiments,the manufacturing process produces sufficiently clean syringe barrels sothat this cleaning step is optional. Thereafter, table 146 rotates tocarry the syringe barrel assemblies 137 to a lubricating station 152where a thin coating of a lubricant is applied to the inner surface ofthe syringe barrel assemblies 137. The lubricant is preferably asilicone oil as known in the art. Table 146 then rotates to carry thesyringe barrel assemblies 137 to a discharge station 154, where thesyringe barrel assemblies 137 are discharged onto a conveyor rail 156and conveyed to housing assembly 116.

In the embodiment illustrated, housing assembly 116 includes an accessopening 129 in side wall 120 to enable an operator sitting on a seat orchair 131 to reach into the housing assembly 116. The opening 129 isdimensioned to enable the operator to perform various manual operationswhile maintaining the workstation area at the desired cleanliness level.In the embodiment illustrated, the operator examines the syringe barrelassemblies 137 and places the assemblies in the tray 84 which is in thetub 92. The operator then places the protective sheet material 102 overthe syringe barrel assemblies 137. The closure sheet 104 is then placedover the tub 92 and the tub is manually placed in housing assembly 118through an opening 158 in side wall 120. In further embodiments, thesyringe barrel assemblies 137 are placed in tub 92 automatically bysuitable machinery.

Within housing assembly 118 is a heated platen 160 for heat sealing theclosure sheet 104 onto tub 92. The platen 160 is lowered onto the sheet104 and the sheet is sealed to the flange 100 of the tub 92 to enclosethe syringe barrel assemblies 137. Since the syringe barrel assemblies137 are now enclosed in protective packaging, the tub can be removedfrom the housing assembly 118 without the risk of contamination of thesyringe barrel assemblies 137. The tub can then be sealed in a plasticbag or other protective outer wrap and placed in suitable shippingcartons. Standard heat sealing and bagging devices are typically used.

Alternatively, the tub package 82 can be transferred from the housingassembly 118 to a further housing assembly 121 serving as asterilization chamber. Sterilization can be, for example, by gamma orbeta radiation, hot air or steam autoclave. In preferred embodiments,the cover sheet 104 is a gas permeable material which is permeable toethylene oxide sterilizing gas. Typically, the tub package 82 is exposedto ethylene oxide for sufficient time to permeate the closure sheet andsterilize the contents thereof. The chamber is then evacuated and purgedwith carbon dioxide or other gas to remove the ethylene oxide. Theplastic bagging operation described above may then be performed.

In the embodiment illustrated in FIG. 7, sterilization chamber 121 isconnected in line with housing assembly 118 to receive the tub package82. Alternatively, the tub packages 82 are transferred to asterilization chamber at a different location. Sterilization can also beperformed after placing the packages 82 in suitable shipping cartons.

The apparatus of FIG. 7 is intended to be exemplary of one embodiment ofthe invention. In this embodiment, the housing assemblies definedifferent work stations and are in modular form for assembly anddisassembly. In further embodiments, apparatus 108 can be a singlehousing enclosing all of the work stations.

Referring to FIG. 9, a flow chart depicts the method of assembly of thetub package 82. Clean syringe barrels are fed from a supply as indicatedin block 170, and clean tip closures are fed from a supply as indicatedin block 172. The syringe barrels can be fed to an optional printstation as indicated in block 177. Optional needle cannulas as indicatedin block 171, needle shields as indicated in block 173 and Luer lockcollars as indicated in block 175 are also fed from a supply. Thesyringe barrels and syringe components are supplied to a locallycontrolled environment for assembly of the components to the syringebarrels indicated in block 174. The syringe barrel and tip closureassemblies are conveyed through an optional stream of clean, ionized airto remove particulates from the outer surface of the syringe barrelassemblies as indicated in block 176. The syringe barrel assemblies arethen passed to a station where the inner surfaces of the syringe barrelsare cleaned with filtered, ionized air and vacuum as indicated in block178, and to a lubricating station where a lubricant is applied to theinner surfaces as indicated in block 180.

The lubricated syringe assemblies are placed in the tray and tub asindicated in block 182, followed by the addition of a protective sheetas indicated in block 184 and an outer cover sheet as indicated in block186. The tub package is then placed in a heat sealer to seal the coversheet to the tub as indicated in block 188. The sealed tub is enclosedin a plastic bag as indicated in block 190, followed by sterilization asindicated in block 192.

In a further embodiment, a housing assembly substantially as describedabove encloses a container filling device for filling the medicalcontainer with the desired substance. The container can be a suitablemedical container such as a vial or syringe barrel. The housing assemblyincludes an inlet for receiving the container and an air or water washdevice as needed for cleaning the container. The filling device fillsthe clean containers and attaches a suitable closure to close thecontainer. The cleaning, filling and assembling devices can be enclosedin a single housing assembly or enclosed in separate housing assembliesconnected together in series by chutes, tunnels or other enclosures. Thedrug containers can be molded plastic or formed glass which are capturedimmediately after molding or forming in the housing assembly to maintainthe clean and low bio-burden levels. The molding and forming devices canbe positioned next to the housing assembly and connected thereto by aclosed conveyor, tunnel or chute. In further embodiments, the molding orforming device can be enclosed in a housing assembly to define anenvironmentally controlled area to maintain cleanliness standards.

The package 82 of syringe barrel assemblies and the packaged stopperscan be transferred to an enclosed housing assembly for filling thesyringe barrel and assembling a prefilled syringe. Each syringe barrelis filled with a predetermined amount of a substance while held in aclosed, clean containment area. The containment area is then evacuatedand the plunger and stopper assembly is positioned in the open end ofthe syringe barrel. The vacuum is then released and the plunger is drawninto the syringe barrel by the vacuum remaining within the barrel.Alternatively, the plunger and syringe barrel can be assembled by a venttube stoppering process as known in the art. Thereafter, the assembledsyringes are packaged as prefilled syringes and sold for use by healthcare providers.

FIG. 10 illustrates a flow chart for a method of producing a prefilledsyringe. Referring to FIG. 10, a supply of preformed syringe barrels areformed in a syringe barrel molding machine indicated by block 220. Themolded syringe barrels are transferred into a locally controlledenvironment indicated by 222 preferably without any additional cleaningor sterilizing steps. It is preferred that the transferring of moldedsyringe barrels to the locally controlled environment be immediate. Thesyringe barrels are washed with air to remove particulates and coatedwith a lubricant such as silicone lubricating oil on the inner surfaceas indicated by block 224. A supply of tip caps indicated by block 226is fed into the locally controlled environment 222. The tip caps are airwashed as indicated by block 228. The cleaned tip caps and syringebarrels are conveyed to an assembly device indicated by block 230 wherethe tip caps are assembled onto the syringe barrel to close the tip ornozzle of the syringe barrel. The syringe barrel assemblies are thenconveyed to a filing station indicate by block 232 where the syringebarrel is filled with a substance as defined herein.

A supply of stoppers indicated by block 234 is transferred to a washingstation indicated by block 236 where a silicone lubricant is applied tothe stoppers. The lubricated stoppers are then delivered to a transferfeed device indicated by block 240 within the locally controlledenvironment 222. The stoppers are then assembled with the filled syringebarrels indicated by block 242 to close the syringe. In particular, thestopper is inserted into the open proximal receiving end of the syringebarrel. The prefilled syringes are preferably inspected for defects asindicated by block 244 and discharged form the locally controlledenvironment 222, sterilized as indicated by block 246 and packagedeither individually or in bulk for transporting indicated by block 248.Suitable sterilization methods include heat, steam, radiation and gassterilization as known in the art. In some uses, for example, if thesyringe is to be used in a surgical procedure, the sterilization stepshould occur after the syringe is packaged. It is also within thepurview of the present invention to include sterilization of the syringeboth before and after packaging.

In the method of FIG. 10, the syringe barrels are breach filled and thetip cap is coupled to the barrel before filling. It will be understoodby those skilled in the art that a stopper and/or syringe plunger can becoupled to the syringe barrel before filling and the syringe barrelfilled through the tip or nozzle. Thereafter, a tip cap or needle can beattached to the filled syringe barrel to close the tip. Accordingly,medical containers such as the syringe can be filled by known fillingmethods. Exemplary methods for filling syringes and other medicalcontainers are disclosed in U.S. Pat. No. 5,620,425 to Hefferman et al.,U.S. Pat. No. 5,597,530 to Smith et al., U.S. Pat. No. 5,537,042 toDeHaen, U.S. Pat. No. 5,531,255 to Vacca, U.S. Pat. Nos. 5,519,984 and5,373,684 to Veussink et al., U.S. Pat. No. 5,256,154 and 5,287,983 toLiebert et al. and U.S. Pat. No. 4,718,463 to Jurgens, Jr. et al., whichare hereby incorporated by reference in their entirety.

The locally controlled environment of the illustrated embodimentsincludes assembly machinery for producing bulk packaging of syringebarrel assemblies, filling syringe barrels to form prefilled syringesand to produce prefilled drug containers. It will be appreciated thatother medical containers can be assembled, constructed or packaged inthe locally controlled environment. Examples of containers which can bepackaged including various drug containers, vials, ampoules or othercontainers where a clean environment is required during the processingstep. In addition, the cleanliness standard for the locally controlledenvironment is determined by the air filtration system to obtain asufficiently low particulate and pyrogen level as required. In theembodiment disclosed, the HEPA filters are sufficient to maintain aClass 100 cleanliness standard in each of the housing assemblies. Infurther embodiments, the HEPA filters can be selected to attain Class10, Class 10,000 or Class 100,000 cleanliness conditions.

FIG. 11 illustrates a second embodiment of the manufacturing and packingof medical appliances. The assembly is similar to the embodiment of FIG.8 except that assembly and packaging apparatus 108′ is contained in aclean room 250. In this embodiment, similar components are identified bythe same reference number with the addition of a prime. Glass syringebarrels 12′ are manufactured in a glass forming apparatus 160′. Thesyringe barrels 12′ are conveyed by conveyor 164′ to an annealing oven162′. A closed tunnel 168′ supporting a conveyor 170′ delivers thesyringe barrels 12′ to a clean room 250. The clean room can be astandard clean room having suitable air blowers, HEPA filters,temperature and antistatic controls to maintain the cleanliness levelswithin prescribed limits determined by the selected class.

The glass syringe barrels are conveyed through an opening 252 in theclean room 250 and delivered to the assembly and packaging apparatus108′. The syringe barrels can be further cleaned, assembled with syringecomponents and packaged in trays and tubs as in the previous embodiment.Optionally, the syringe barrels can be filled to produce prefilledsyringes before packaging. The packaged syringe barrels 82′ are thenplaced in cartons or other shipping containers for shipping to theultimate consumer. It will be understood molded plastic drug containerscan be molded and captured immediately after molding in a similar cleanroom where the drug containers can be filled and/or packaged.

Although certain embodiments have been selected to illustrate theinvention, it will be apparent to one skilled in the art that otherembodiments can be used without departing from the scope of theinvention. For example, processes within the scope of the invention canbe used with either glass or plastic syringe barrels through thechanging of conditions to accommodate the requirements of glass orplastic while still following the process steps.

What is claimed is:
 1. A method of producing a prefillable syringecomprising the steps of: forming a plurality of clean syringe barrels ina glass forming device for shaping a cylindrical glass tube into syringebarrels having a first open end for receiving a syringe plunger and asecond open end for discharging contents from said syringe barrel,transferring said syringe barrels to an environmentally controlled areato maintain a predetermined cleanliness level, and cleaning said syringebarrels by directing a filtered air stream to loosen particulates fromat least one surface of said syringe barrels and applying a vacuum toremove said loosened particulates from said syringe barrels within saidenvironmentally controlled area.
 2. The method of claim 1, furthercomprising the steps of: enclosing said syringe barrels in a container,and sterilizing said container.
 3. The method of claim 2, wherein saidsterilizing step comprises exposing said container to either gammaradiation, beta radiation, ethylene oxide, hot air, steam or asterilizing gas.
 4. The method of claim 1, wherein said method comprisesheating said syringe barrels to an annealing temperature tosimultaneously anneal and clean said syringe barrels.
 5. The method ofclaim 1, further comprising the step of enclosing said forming device ina locally controlled area to maintain a predetermined cleanliness level.6. The method of claim 1, further comprising the steps of forming anarray of said syringe barrels, placing said array in a container, andclosing and sealing said container to form packaged syringe barrels. 7.The method of claim 6, further comprising the step of positioning aprotective sheet over said array of syringe barrels in said containerbefore applying a cover sheet to said container to seal said container.8. The method of claim 6, further comprising the step of applying acoating of a lubricant to an inner surface of said syringe barrel. 9.The method of claim 1, further comprising the steps of applying a tipcap to close said second open end of said syringe barrel, filling saidsyringe barrel with a substance, applying a stopper to said first openend of said syringe barrel to form a prefilled syringe.
 10. The methodof claim 9, wherein the step of filling said syringe barrel with thesubstance including a substance selected from the group consisting ofsaline solutions, flush solutions or contrast agents, pharmaceuticalagents and vaccines, in either a dry or liquid state.
 11. The method ofclaim 1, wherein said air stream comprises ionized air.
 12. The methodof claim 1, wherein said forming step includes forming said syringebarrel by heating a glass tube to a temperature of about 760° C. to1100° C.
 13. The method of claim 12, further comprising the step ofannealing said syringe barrel at a temperature of at least about 560° C.14. The method of claim 12, wherein said forming step comprises heatinga first end of said glass tube to a temperature whereby said glass tubeis pliable and shaping said first end to form a flange extendingsubstantially radially outward from a center axis of said glass tube.15. The method of claim 14, further comprising the steps of heating asecond end of said glass tube to a temperature whereby said glass tubeis in a pliable state and shaping said second end for receiving acannula needle.
 16. The method of claim 14, wherein said forming stepincludes heating a second end of said glass tube to a temperaturewhereby said glass tube is in a pliable state and shaping said secondend into a nozzle tip for receiving a needle, and further comprising thestep of securing a needle in the nozzle tip by an adhesive.
 17. Themethod of claim 16, further comprising the step of coupling a protectiveplastic needle sheath having an open end with said nozzle tip, saidprotective plastic needle sheath having a hollow, substantiallycylindrical shape and being dimensioned to receive said needle so thatsaid protective plastic needle sheath contacts and closes off a tip ofthe needle to prevent leakage.
 18. The method of claim 1, wherein saidenvironmentally controlled area maintains a cleanliness level of aboutClass
 100. 19. The method of claim 1, wherein said environmentallycontrolled area comprises at least one housing assembly having an airblower and a HEPA filter coupled to said air blower to filter airentering said at least one housing assembly.
 20. The method of claim 13,wherein said at least one housing assembly is maintained at a positiveinternal pressure to prevent unfiltered air from entering said housingassemblies.
 21. The method of claim 1, further comprising the steps ofproviding a plurality of collars to said environmentally controlledarea; and snapping each said collar to said second open end of eachsyringe barrel.
 22. A method of producing prefillable syringe barrelassemblies in one or more housing assembly for maintaining apredetermined cleanliness level comprising the steps of: forming aplurality of clean syringe barrels in a forming device, said syringebarrels each having a first open end for receiving a syringe plunger anda second open end for discharging contents from said syringe barrels,with the second open end being formed into a nozzle tip for receiving aneedle; supplying a plurality of needles and securing said needles inthe nozzle tips of said syringe barrels by an adhesive; supplying aplurality of protective plastic needle sheaths and coupling theprotective plastic needle sheaths to said nozzle tips of said syringebarrels to form syringe barrel assemblies; transferring said syringebarrel assemblies to at least one housing assembly for maintaining apredetermined cleanliness level; directing a filtered air stream toloosen any particulates from at least one surface of said syringebarrels assemblies and applying a vacuum to remove loosened particulatesfrom said syringe barrel in said at least one housing assemblytransferring said syringe barrel assemblies to at least another housingassembly; and packaging at least one or more of said syringe barrelassemblies in a package in said at least another housing assembly. 23.The method of claim 22, wherein said step of forming said syringebarrels comprises supplying a cylindrical glass tube to said formingdevice and heating said first open end of said glass tube to atemperature whereby said glass tube is pliable and forming a flangeabout said first open end and heating said second open end of said glasstube to a temperature whereby said glass tube is pliable and formingsaid nozzle tip at said second open end.
 24. The method of claim 23,wherein said protective plastic needle sheaths each have a hollow,substantially cylindrical shape and are dimensioned to receive saidneedle, and said coupling step includes contacting protective plasticneedle sheaths with said needle so that said protective plastic needlesheath closes off a tip of each of the needles to prevent leakage. 25.The method of claim 23, further comprising the step of filling saidsyringe barrels with a desired substance and coupling a closure memberto said syringe barrels to close said first open ends of said syringebarrels.
 26. The method of claim 22, wherein said air stream comprisesionized air.
 27. The method of claim 22, further comprising the steps offilling each said syringe barrel with a substance selected from thegroup consisting of saline solutions, flush solutions or contrastagents, or pharmaceutical agents and vaccines, in either a dry or liquidstate and coupling a closure member to said syringe barrels to close thefirst open ends of said syringe barrels.
 28. The method of claim 22,further comprising the step of sterilizing said package in at leastanother housing assembly.
 29. The method of claim 45, wherein saidpackaging step includes forming an array of said syringe barrelassemblies, and placing said array in a container having a closedbottom, side walls and an open top end, applying a cover sheet to saidcontainer to entirely close said container, and sealing said cover sheetto said container.